Our research focuses on charactering the structures of macromolecular machinery in their cellular context using three-dimensional (3D) cryo-electron tomography (cryoET) and correlative light and electron microscopy. Structures of intracellular macromolecular complexes are usually heterogeneous and dynamic, relying largely on interactions with other cellular components. Using cryoET to determine the structure of cellular machinery inside the cell avoids damage to the complexes during purification, captures snapshots of the complex while in action, and provides information on cross-talk of the complexes with their cellular partners during biological processes. Our current research interest includes:
Huntington's disease: structure and organization of protein aggregates; 3D architecture of the diseased cells under misfolded protein aggregation stress
Huntington's disease (HD) is an inherited neurodegenerative disease characterized by progressive motor, cognitive, and psychiatric deterioration. In HD neurons, the formation, abundance and persistence of mutant huntingtin (mHTT) aggregation species are correlated with neurodegeneration, however, the identity of toxic species and the structural basis for mHTT toxicity are not clear. Multiple cellular pathways have been implicated in the pathogenesis of HD, including protein homeostasis, calcium signaling, mitochondrial dysfunction, and vesicular transport and recycling. Using cryoET to directly visualize mHTT and cellular components involved in these cellular pathways will provide insights to HD pathogenesis and potential therapeutic targets.
Structural biology of phage/virus maturation
Using the new phase contrast technology, we have visualized multiple assembly intermediates of cyanobacterial phages inside the host at different stages of maturation. Current studies focus on further unraveling the details of capsid accessory protein assembly and genome packaging.